Synthetic psychoactive drugs (SPDs) are substances that are specifically designed to mimic the actions of known abused drugs. Yet, SPDs typically skirt the legal definition of an illegal substance and can also pose a public health threat. It can be argued that a major trend throughout the history of drug use and abuse is the increased hazards associated with the use of more potent drugs, either purified plant materials or new synthetic compounds. Beginning in 1979, the illicit synthesis of drugs was elevated to an extraordinarily sophisticated level. A number of overdose victim's deaths were attributed to heroin, however, seized samples contained no heroin, rather the victims were buying from drug dealers selling China White, alpha-methylfentanyl. The fentanyls are a large family of highly potent synthetic narcotic analgesics. They have all the properties of the opiates, however, they are 50-100 times more potent than morphine; yet, are chemically unrelated and therefore do not cross-react with reagents used in opiate screening tests. The recent deaths in Rhode Island, New Jersey, Pennsylvania and the Southeast all associated with the newest fentanyl, acetyl fentanyl, have brought this designer drug family in the public forefront again. Reasons for fentanyl resurfacing are tied to a decline in heroin purity, a need to increase potency and cost efficient preparation. Simply stated designer fentanyl's can be synthesized at a single location and because of its potency a single gram could be formulated (cut) into many thousand, perhaps a million doses. Preventing the distribution of such small amounts of a pure drug is exceedingly difficult. Thus, while drug control efforts will need to continue, so will efforts to teat SPD abuse/addiction. NIDA has issued a specific program announcement (PAR-14-105) entitled synthetic psychoactive drugs and strategic approaches to counteract their deleterious effects. Although, antibody therapies have been examined for treating drugs of abuse such as cocaine, nicotine, methamphetamine and heroin no antibody effort has ever been attempted with regards to an SPD. Accordingly, we plan to investigate antibodies against fentanyl and its designer congeners. We will take two approaches to counter these mu-receptor opioid drugs, however, both will be grounded upon unique hapten designs that will be critical in producing antibodies that cannot only counter fentanyl but also the common street analogues of this synthetic opioid. Once hapten synthesis is secure we will examine both active and passive vaccine strategies. Antibodies from the latter will come via a combination of antibody-phage/yeast display technology, here we will use a selection process wherein cross-reactive human antibodies to the 1-(2-phenethyl)-4-(N-propionylanilino) piperidine drug class will be secured through unique fentanyl tagged fluorophores coupled to antibody-yeast FACS screening and analysis. Finally, a metric will be needed to judge the value of both types of vaccines for treating fentanyl's physiological processes; we will look at antinociceptive effects a each vaccine can be evaluated in a drug-dose dependent manner.